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J. Biol. Chem., Vol. 281, Issue 40, 29431-29435, October 6, 2006

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Brain-derived Neurotrophic Factor (BDNF)-induced Synthesis of Early Growth Response Factor 3 (Egr3) Controls the Levels of Type A GABA Receptor4 Subunits in Hippocampal Neurons^*

Daniel S. Roberts¹²³, Yinghui Hu¹², Ingrid V. Lund, Amy R. Brooks-Kayal^¶, and Shelley J. Russek⁴

From the Laboratory of Molecular Neurobiology, Department of Pharmacology, Boston University School of Medicine, Boston, Massachusetts 02118, the Neuroscience Graduate Group, University of Pennsylvania, Philadelphia, Pennsylvania 19104, and the ^¶Division of Neurology, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Altered function of -aminobutyric acid type A receptors (GABA_ARs) in dentate granule cells of the hippocampus has been associated with temporal lobe epilepsy (TLE) in humans and in animal models of TLE. Such altered receptor function (including increased inhibition by zinc and lack of modulation by benzodiazepines) is related, in part, to changes in the mRNA levels of certain GABA_AR subunits, including 4, and may play a role in epileptogenesis. The majority of GABA_ARs that contain 4 subunits are extra-synaptic due to lack of the 2 subunit and presence of . However, it has been hypothesized that seizure activity may result in expression of synaptic receptors with altered properties driven by an increased pool of 4 subunits. Results of our previous work suggests that signaling via protein kinase C (PKC) and early growth response factor 3 (Egr3) is the plasticity trigger for aberrant 4 subunit gene (GABRA4) expression after status epilepticus. We now report that brain derived neurotrophic factor (BDNF) is the endogenous signal that induces Egr3 expression via a PKC/MAPK-dependent pathway. Taken together with the fact that blockade of tyrosine kinase (Trk) neurotrophin receptors reduces basal GABRA4 promoter activity by 50%, our findings support a role for BDNF as the mediator of Egr3-induced GABRA4 regulation in developing neurons and epilepsy and, moreover, suggest that BDNF may alter inhibitory processing in the brain by regulating the balance between phasic and tonic inhibition.

Received for publication, June 27, 2006 , and in revised form, August 2, 2006.

^* This work was supported by National Institutes of Health/NINDS Grant NS050393. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to the work.

² Both authors supported by a training fellowships from the Program in BioMedical Neuroscience, Boston University School of Medicine.

³ Supported by a T32 from the National Institutes of Health/NIGMS.

⁴ To whom correspondence should be addressed: Laboratory of Molecular Neurobiology, Dept. of Pharmacology, Boston University School of Medicine, 715 Albany St., Boston, MA 02118. Tel.: 617-638-4319; Fax: 617-638-4329; E-mail: srussek{at}bu.edu.

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